Diabetes is a metabolic disease characterized by high levels of sugar in the blood. The two most prevalent types of diabetes are Type 1 diabetes mellitus (T1DM) and Type 2 diabetes mellitus (T2DM). Type 1, or insulin-dependent diabetes mellitus (IDDM), is a chronic autoimmune disease characterized by the extensive loss of beta cells in the pancreatic islets, which produce insulin. Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), develops when muscle, fat and liver cells fail to respond normally to insulin (insulin resistance). In particular, Type 2 diabetes has become an epidemic, driven by increases in obesity and a sedentary lifestyle, and the general aging of the populations in many countries. In recent clinical practice, it has become increasingly difficult to distinguish T1DM from T2DM as many children with T1DM are overweight at diagnosis, and a considerable proportion of physician-diagnosed T2DM youth have evidence of pancreatic autoimmunity (Badaru, A. and Pihoker, C. “Type 2 diabetes in childhood: clinical characteristics and role of beta-cell autoimmunity,” Curr. Diab. Rep., 2012, 12, 75-81). In 2011, more than 346 million people worldwide were affected by diabetes.
Recent studies have demonstrated that TGF-β plays a role in pancreatic islet function and diabetes development (Moritani, M. et al. “Abrogation of autoimmune diabetes in nonobese diabetic mice and protection against effector lymphocytes by transgenic paracrine TGF-β1,” J. Clin. Invest., 1998, 102, 499-506; Olivieri, A. et al. “Serum transforming growth factor β1 during diabetes development in non-obese diabetic mice and humans,” Clin. Exp. Immunol., 2010, 162, 407-414). For example, an islet-specific pulse of TGF-β expression for one week has been shown to delay diabetes development in NOD mice (Wållberg, M. et al. “An islet-specific pulse of TGF-β abrogates CTL function and promotes β cell survival independent of Foxp3+ T cells,” J. Immunol., 2011, 186, 2543-2551), a commonly used animal model of type 1 diabetes (Roep, B. O. et al. “Satisfaction (not) guaranteed: re-evaluating the use of animal models of type 1 diabetes,” Nat. Rev. Immunol., 2004, 4, 989-997). TGF-β1 was effective not only in curing diabetes in diabetic NOD mice and blocking islet destructive autoimmunity, but also in inducing islet regeneration (Luo, X. et al. “Systemic transforming growth factor-β gene therapy induces Foxp3+ regulatory cells, restores self-tolerance, and facilitates regeneration of beta cell function in overtly diabetic nonobese diabetic mice,” Transplantation, 2005, 79, 1091-1096). Hence, therapeutic interventions along this pathway, may not only stop the progression of the disease, but might even restore function (i.e., adequate insulin production) after onset of hyperglycemia.
The TGF-βs 1-3 are involved in a variety of biological functions including cell growth, organ development, fibrogenesis, and regulation of immune cells. TGF-β1 is the predominant form expressed in the immune system, and it is now well-recognized as a critical regulator in immune responses that can dampen T cell responses (Li, M. O. and Flavell, R. A. “TGF-beta: a master of all T cell trades,” Cell, 2008, 134, 392-404). Specifically, TGF-β1 binds a heterodimeric transmembrane serine/threonine kinase receptor containing two subunits, TGF-β1 R1 and TGF-β1 R2. Upon ligand binding, the TGF-β1 R1 receptor is phosphorylated by the constitutively active TGF-β1 R2 receptor and signal is propagated to the nucleus by proteins belonging to the SMAD family. Activated TGF-β1 R1 directly phosphorylates SMAD2 and SMAD3 proteins, which then interact with SMAD4. The complex of SMAD2/SMAD3/SMAD4 translocates to the nucleus and modulates the transcription of certain genes. SMAD7 is another member of this protein family that acts as a general antagonist for TGF-β through negative-feedback mechanisms (Yan, X. and Chen, Y. G. “Smad7: not only a regulator, but also a cross-talk mediator of TGF-beta signalling,” Biochem. J., 2011, 434, 1-10).
Studies have demonstrated that SMAD7 plays a role in diabetes and β-cell function. SMAD7, an intracellular protein, has been shown to interfere with binding of SMAD2/SMAD3 to the TGF-β1 R1 preventing phosphorylation and activation of these proteins, leading to inhibition of TGF-β1 mediated-signaling. Expression of SMAD7 in pancreatic β-cells has been shown to disrupt TGF-β signaling and induce reversible diabetes mellitus (Smart, N. G. et al. “Conditional expression of Smad7 in pancreatic beta cells disrupts TGF-beta signaling and induces reversible diabetes mellitus,” PLoS Biol., 2006, 4, e39). Furthermore, results in NOD mice also implicate the Smad2 and TGF-β signaling pathway in activated dendritic cells in diabetogenesis, and there is evidence from human genome-wide association studies supporting a role for Smad7 in human type 1 diabetes (Rook, S. M. et al. “Smad2: A candidate gene for the murine autoimmune diabetes locus Idd21.1,” J. Clin. Endocrinol. Metab., 2011, 96, E2072-E2077). Since TGF-β1 has been shown to contribute to the suppression of cytokine production, the inhibition of T cell response, and the induction of regulatory T cells (Treg) (Kawamoto, K. et al. “Transforming growth factor beta 1 (TGF-β1) and rapamycin synergize to effectively suppress human T cell responses via upregulation of FoxP3+ Tregs,” Transpl. Immunol., 2010, 23, 28-33), SMAD7 modulation could also be beneficial in islet transplantation by supporting graft function, limiting toxicity, and preventing immune rejection.
Thus, there is an unmet need for new therapies in diabetes and pancreatic islet transplantation.